Hippocampal BDNF Expression in a Tau Transgenic Mouse Model

Max-Planck Institute für Biologie des Alterns/Max-Planck Institute for Biology of Ageing, Köln, Germany.
Current Alzheimer research (Impact Factor: 3.89). 01/2012; 9(4):406-10. DOI: 10.2174/156720512800492468
Source: PubMed


Alzheimer's disease (AD) is a neurodegenerative disorder characterized by extracellular accumulation of amyloid deposits and intracellular neurofibrillary tangles (NFT) composed of hyperphosphorylated Tau proteins. Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor playing a critical role in hippocampal synaptic plasticity and memory and whose levels have been shown reduced in AD brains. While recent data support a pivotal role of β-amyloid peptides towards BDNF decrease, whether Tau pathology impacts on BDNF expression remains unknown so far. In the present study, we have evaluated this relationship using quantitative PCR, Western blot and ELISA in the THY-Tau22 transgenic strain, known to display a progressive development of both hippocampal AD-like Tau pathology and memory impairments. We observed that Tau pathology was not associated with down-regulation of BDNF at the protein and mRNA levels in this model, suggesting that the alteration of BDNF homeostasis observed in AD patients' brains might rather be ascribed to amyloid pathology.

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    • "Conversely, relationships between Tau pathology, which occurs early during the normal process of aging (Braak et al., 2011), and BDNF expression and function are far less understood. Recently, we reported the absence of BDNF mRNA and protein down-regulation in a Tau transgenic mouse model – the THY-Tau22 model – (Burnouf et al., 2012), which exhibits AD-like hippocampal Tau pathology paralleling hippocampus-dependent memory impairments (Schindowski et al., 2006; Belarbi et al., 2011; Van der Jeugd et al., 2011). However, as hyperphosphorylated Tau species are relocalized to the somatodendritic compartment in AD and Tau transgenic mice (Schindowski et al., 2006; Ballatore et al., 2007; Hoover et al., 2010; Ittner et al., 2010), it remains uncertain whether beyond its basal expression, synaptic effects mediated by BDNF would be affected. "
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    ABSTRACT: While the spatiotemporal development of Tau pathology has been correlated with occurrence of cognitive deficits in Alzheimer's patients, mechanisms underlying these deficits remain unclear. Both brain-derived neurotrophic factor (BDNF) and its tyrosine kinase receptor TrkB play a critical role in hippocampus-dependent synaptic plasticity and memory. When applied on hippocampal slices, BDNF is able to enhance AMPA receptor-dependent hippocampal basal synaptic transmission through a mechanism involving TrkB and NMDA receptors (NMDAR). Using THY-Tau22 transgenic mice, we demonstrated that hippocampal Tau pathology is associated with loss of synaptic enhancement normally induced by exogenous BDNF. This defective response was concomitant to significant memory impairments. We show here that loss of BDNF response was due to impaired NMDAR function. Indeed, we observed a significant reduction of NMDA-induced field excitatory post-synaptic potential depression in the hippocampus of Tau mice together with a reduced phosphorylation of NR2B at the Y1472, known to be critical for NMDAR function. Interestingly, we found that both NR2B and Src, one of NR2B main kinase, interact with Tau and are mislocalized to the insoluble protein fraction rich in pathological Tau species. Defective response to BDNF was thus likely related to abnormal interaction of Src and NR2B with Tau in THY-Tau22 animals. These are the first data demonstrating a relationship between Tau pathology and synaptic effects of BDNF and supporting a contribution of defective BDNF response and impaired NMDAR function to the cognitive deficits associated with Tauopathies. © 2012 The Authors Aging Cell © 2012 Blackwell Publishing Ltd/Anatomical Society of Great Britain and Ireland.
    Aging cell 10/2012; 12(1). DOI:10.1111/acel.12018 · 6.34 Impact Factor
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    ABSTRACT: Alterations in the expression and signaling of brain-derived neurotrophic factor (BDNF) and the precursor to nerve growth factor (NGF), proNGF, play a role in the neuronal and cognitive dysfunction of Alzheimer's disease. Aggregated amyloid-β has been shown to down-regulate specific BDNF transcripts in Alzheimer's disease, but the role of tau pathology in neurotrophin dysregulation has not been investigated. We measured levels of BDNF mRNA and protein using real-time quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay and proNGF protein using Western blotting in parietal cortex of subjects with tauopathies, neurodegenerative diseases exhibiting tau pathology without amyloid-β accumulation. We observed a significant increase in the level of proNGF protein in Pick's disease and a significant decrease in BDNF mRNA and protein levels in Pick's disease and corticobasal degeneration, but no neurotrophin alterations in progressive supranuclear palsy. The decrease in total BDNF mRNA levels in these tauopathies was predominantly due to down-regulation of transcript IV. These findings implicate tau pathology in neurotrophin dysregulation, which may represent a mechanism through which tau confers toxicity in Alzheimer's disease and related non-Alzheimer's dementias.
    Neurobiology of aging 10/2013; 35(4). DOI:10.1016/j.neurobiolaging.2013.08.029 · 5.01 Impact Factor
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    ABSTRACT: Full text: Consumption of caffeine, a non-selective adenosine A2A receptor (A2AR) antagonist, reduces the risk of developing Alzheimer's disease (AD) in humans and mitigates both amyloid and Tau burden in transgenic mouse models. However, the impact of selective A2AR blockade on the progressive development of AD-related lesions and associated memory impairments has not been investigated. In the present study, we removed the gene encoding A2AR from THY-Tau22 mice and analysed the subsequent effects on both pathological (Tau phosphorylation and aggregation, neuro-inflammation) and functional impairments (spatial learning and memory, hippocampal plasticity, neurotransmitter profile). We found that deleting A2ARs protect from Tau pathology-induced deficits in terms of spatial memory and hippocampal long-term depression. These effects were concomitant with a normalization of the hippocampal glutamate/gamma-amino butyric acid ratio, together with a global reduction in neuro-inflammatory markers and a decrease in Tau hyperphosphorylation. Additionally, oral therapy using a specific A2AR antagonist (MSX-3) significantly improved memory and reduced Tau hyperphosphorylation in THY-Tau22 mice. By showing that A2AR genetic or pharmacological blockade improves the pathological phenotype in a Tau transgenic mouse model, the present data highlight A2A receptors as important molecular targets to consider against AD and Tauopathies.
    Molecular Psychiatry 12/2014; DOI:10.1038/mp.2014.151 · 14.50 Impact Factor

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